oxygenation of arachidonic acid (AA) through a cytochrome P-450- linked system of enzymes is firmly established in mammalian kidney. The resulting oxygenated fatty acids include epoxyeicosatrienoic acids (EETs), their diol hydration products, and w/w-l oxygenated derivatives. These compounds possess a number of biologic effects including inhibition of sodium and potassium transport in renal epithelia, inhibition of Na+/K+-ATPase activity, relaxation of vascular smooth muscle, and antagonism of vasopressin-stimulated water transport. The potential biologic significance of these effects is highlighted by our recent preliminary observations that renal P-450/AA oxygenase activity appears to be markedly stimulated in: 1. Adrenalectomized animals treated with deoxycorticosterone (DOCA), 2. Pregnant rats, 3. Remaining kidney following unilateral nephrectomy, and 4. Kidneys of diabetic rats. The present studies propose to investigate the hypothesis that the up-regulation of this enzyme system plays a role in mediating the dramatic alterations in renal function which characterize these conditions. To this end, use will be made of standard clearance and metabolic balance studies in the chronically catheterized, awake rat preparation, and of clearance and glomerular micropuncture techniques in the anesthetized rat. These techniques will be combined with the bioanalytic and synthetic capacities provided in Projects 2 and 6 and Core B to examine: 1. The changes in renal functional parameters upon exogenous administration of synthetic P-450/AA metabolites. 2. The regulation of this enzyme system in the physiologic and pathophysiologic models listed above and the correlation of the changes in enzyme activity and end-product generation with the accompanying functional alterations. In the latter studies, use will also be made of newly developed specific inhibitors of the P-450/AA enzyme system. In summary, this project will investigate, at the intact organ and single nephron levels, the functional relevance of the observations made at the cellular and isolated tubule levels, relying extensively on Project 6 as a synthetic source of compounds and on Project 2 to establish correlations between the rates of endogenous production of P-450/AA metabolites, and renal functional adaptations to physiologic and pathophysiologic stimuli.

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Vanderbilt University Medical Center
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